The major goals of this project are to define the defects in lymphocyte differentiation or function associated with immune deficiency diseases, lymphoid malignancies, and disorders of immunoregulation. The underlying thesis is that some of the gaps in knowledge about the human immune system can be addressed by the comparative analysis of the normal ontogeny of the immune system and the immune system defects in primary immunodeficiency diseases. Emphasis is on (1) the ontogeny of B cell development in humans, (2) the genetic basis of immunodeficiency, and (3) the influence of gene defects on the differentiation of immunocompetent cells. X-linked agammaglobulinemia (XLA) remains the prototype of primary immunodeficiency diseases. Although the affected gene underlying XLA has been identified, the molecular mechanisms that lead to the disruption of B cell development is still poorly understood. The hypothesis to be tested is that the block in XLA is not an abrupt termination of cell differentiation between the pre-B and B cell stage, but that deviant development is apparent at earlier stages in pre-B cell development. In previously supported work, evidence of a genetic link between the two most common primary immunodeficiency diseases, IgA deficiency (IgAD) and common variable immunodeficiency (CVID), was obtained. In the last year, we have shown that in a large family with multiple affected individuals, genetic susceptibility of IgAD or CVID is associated with the inheritance of gene or genes located near the TNF/LT locus within the class III MHC region. The disease phenotype and prevalence of immunodeficiency in the offspring of IgAD/CVID patients differ in individuals who lack the susceptibility MHC haplotype. Analysis of MHC haplotypes in patients and their families to elucidate which gene in the MHC region is associated with these diseases will be continued. Specific candidate genes in and around the TNF/LT locus are being examined in these families.